The processing and presentation of lipids and glycolipids to the immune system

Vartabedian, Vincent F.; Savage, Paul B.; Teyton, Luc

doi:10.1111/imr.12431

Cited by 36 publications

(30 citation statements)

References 100 publications

(153 reference statements)

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“…16,32 CD1 lipid loading seems to occur in endosomal compartments of many antigen-presenting cells such as epithelial mucosa. In their trafficking and binding to lipid antigens for recognition of T cell receptors, CD1 molecules are assisted by saposins, small lipid transfer proteins that facilitate non-enzymatically the hydrolysis of a variety of glycosphingolipids in lysosomes, 33,34 although the mechanism of this transfer and whether there is a direct CD1-saposin binding is still unknown. As CD1 molecules recycle through cellular compartments, they encounter in addition to saposins other proteins such as Niemann-Pick type C2 protein 35 In any event, we have shown in this work that the lipid-ligand of Pru p 3, perhaps especially its phytosphingosine domain, is presented to iNKT cells by CD1 receptors.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying induction of allergic sensitization by Pru p 3

Tordesillas

Cubells-Baeza

Gómez‐Casado

et al. 2017

Clin Experimental Allergy

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Background Recently, the nature of the lipid-ligand of Pru p 3, one of the most common plant food allergens in Southern Europe, has been identified as a derivative of the alkaloid camptothecin bound to phytosphingosine. However, the origin of its immunological activity is still unknown. Objective We sought to evaluate the role of the Pru p 3 lipid-ligand in the immunogenic activity of Pru p 3. Methods In vitro cultures of different cell types (monocyte-derived dendritic cells (moDCs), PBMCs and epithelial and iNKT-hybridoma cell lines) have been used to determine the immunological capacity of the ligand, by measuring cell proliferation, maturation markers and cytokine production. To study the capacity of the lipid-ligand to promote sensitization to Pru p 3 in vivo, a mouse model of anaphylaxis to peach has been produced and changes in the humoral and basophil responses have been analyzed. Results The lipid-ligand of Pru p 3 induced maturation of moDCsc and proliferation of PBMCs. Its immunological activity resided in the phytosphingosine tail of the ligand. The adjuvant activity of the ligand was also confirmed in vivo, where the complex of Pru p 3-ligand induced higher levels of IgE than Pru p 3 alone. The immunological capacity of the Pru p 3 ligand was mediated by CD1d, as maturation of moDCs was inhibited by anti-CD1d antibodies and Pru p 3-ligand co-localized with CD1d on epithelial cells. Finally, Pru p 3-ligand presented by CD1d was able to interact with iNKTs. Conclusions & Clinical Relevance The Pru p 3 lipid-ligand could act as an adjuvant to promote sensitization to Pru p 3, through its recognition by CD1d receptors. This intrinsic adjuvant activity of the accompanying lipid cargo could be a general essential feature of the mechanism underlying the phenomenon of allergenicity.

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Section: Discussionmentioning

confidence: 99%

Mechanisms underlying induction of allergic sensitization by Pru p 3

Tordesillas

Cubells-Baeza

Gómez‐Casado

et al. 2017

Clin Experimental Allergy

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“…Antigens can be proteins, nucleic acids, 7,8 sugars 9,10 as well as lipids. [11][12][13] So long as there is even marginal affinity of the B-cell receptor (BCR) for an epitope of the immunogen, clonal expansion is launched and ever-improved antibodies are generated.…”

Section: Vaccines That Workmentioning

confidence: 99%

B-cell restriction – an alternative piece to the puzzle

Gershoni

2019

Human Vaccines & Immunotherapeutics

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Effective vaccination is based on three critical aspects of the B-cell response towards infectious agents: (i) that B-cells can generate specific antibodies towards a vast molecular diversity of antigens; proteins, sugars, DNA and lipids. There seems to be no limit to the ability to raise antibodies to everything. (ii) once stimulated, B-cells can perfect their antibodies through affinity maturation to complement every nook and cranny of the epitope and (iii) that the pathogen remains genetically stable and does not change to any great extent. Thus, antibodies produced against the vaccine and subsequent boosts recognize the viral virulent field isolates in future encounters and effectively knock them out. However, some vaccine targets, such as flu virus and HIV, are extremely genetically dynamic. The rapid genetic drift of these viruses renders them moving targets which assist in their ability to evade immune surveillance. Here we postulate that in the case of hyper-variable pathogens the B-cell response actually might be “too good”. We propose that restricting B-cell activities may prove effective in counteracting the genetic diversity of variant viruses such as flu and HIV. We suggest two levels of “B-cell restriction”: (i) to focus the B-cell response exclusively towards neutralizing epitopes by creating epitope-based immunogens; (ii) to restrict affinity maturation of B-cells to prevent the production of overly optimized exquisitely specific antibodies. Together, these “B-cell restrictions” provide a new modality for vaccine design.

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“…This can be attributed to the different trafficking pathways between human and mouse CD1d. While mouse CD1d is mainly found in the lysosomes, human CD1d is often found in late endosomes [14,72]. Thus, it is reasonable to suggest that mouse iNKT cells may be more affected by lysosomal dysfunction.…”

Section: Lysosomal Storage and Nkt Cellsmentioning

confidence: 99%

From Lysosomal Storage Diseases to NKT Cell Activation and Back

Pereira

Ribeiro

Macedo

2017

IJMS

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Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special emphasis was given to Natural Killer T (NKT) cells, a population of lipid-specific T cells that is activated by lipid antigens bound to CD1d (cluster of differentiation 1 d) molecules at the surface of antigen-presenting cells. These cells have important functions in cancer, infection, and autoimmunity and were altered in a variety of LSDs’ mouse models. In some cases, the observed decrease was attributed to defects in either lipid antigen availability, trafficking, processing, or loading in CD1d. Here, we review the current knowledge about NKT cells in the context of LSDs, including the alterations detected, the proposed mechanisms to explain these defects, and the relevance of these findings for disease pathology. Furthermore, the effect of enzyme replacement therapy on NKT cells is also discussed.

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The processing and presentation of lipids and glycolipids to the immune system

Cited by 36 publications

References 100 publications

Mechanisms underlying induction of allergic sensitization by Pru p 3

Mechanisms underlying induction of allergic sensitization by Pru p 3

B-cell restriction – an alternative piece to the puzzle

From Lysosomal Storage Diseases to NKT Cell Activation and Back

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